Glutamate is the maj or amino acid neurotransmitter in the mammalian central nervous system. Glutamate plays a major role in numerous physiological functions, such as learning and memory but also sensory perception, development of synaptic plasticity, motor control, respiration, and regulation of cardiovascular function. Furthermore, glutamate is at the centre of several different neurological and psychiatric diseases, where there is an imbalance in glutamatergic neurotransmission.
Glutamate mediates synaptic neurotransmission through the activation of ionotropic glutamate receptor channels (iGluRs), and the NMDA, AMPA and kainate receptors which are responsible for fast excitatory transmission.
In addition, glutamate activates metabotropic glutamate receptors (mGluRs) which have a more modulatory role that contributes to the fine-tuning of synaptic efficacy.
Glutamate activates the mGluRs through binding to the large extracellular amino-terminal domain of the receptor, herein called the orthosteric binding site. This binding induces a conformational change in the receptor which results in the activation of the G-protein and intracellular signaling pathways.
The mGluR2 subtype is negatively coupled to adenylate cyclase via activation of Gαi-protein, and its activation leads to inhibition of glutamate release in the synapse. In the central nervous system (CNS), mGlu2 receptors are abundant mainly throughout cortex, thalamic regions, accessory olfactory bulb, hippocampus, amygdala, caudate-putamen and nucleus accumbens.
Activating mGluR2 was shown in clinical trials to be efficacious to treat anxiety disorders (for studies with orthosteric mGlu2/3 agonists, see Michelson et al.
Neuropharmacology 2005, 49(S1), 84-257; Dunayevich et al.
Neuropsychopharmacology 2008, 33(7), 1603-10), LY354740 had been previously evaluated in non-clinical and clinical model systems predicting utility in the treatment of anxiety disorders beyond generalized anxiety depression (GAD), e.g. panic (see Dunayevich et al. 2008). Non-clinical studies, suggest a role for both mGlu2 and mGlu3 receptors in anxiolysis (Linden et al. Neuropharmacology 2005, 49, 120-134) whilst it has been suggested that positive allosteric modulation of the mGluR2 may be sufficient for an anxiolytic effect (Johnson et al. Psychopharmacology (Berl) 2005, 179(1), 271-283).
In addition, activating mGluR2 was shown to be potentially efficacious for the treatment of
(a) schizophrenia (Patil et al. Nat Med 2007, 13(9), 1102-7); later studies however, do not support treatment of acute exacerbations of schizophrenia with an mGluR2 agonist or allosteric modulator (Adams et al. BMC Psychiatry 2013, 13(1), 143; Kinon et al. J Clin Psychopharmacol. 2013, 31(3), 349-55; Litman et al. (2013) NCDEU Meeting (abstract)) but do not exclude application for other specific symptom clusters (e.g. negative symptoms (Kent et al. “Safety, tolerability and potential therapeutic efficacy of a novel glutamate modulator as adjunctive treatment in patients with schizophrenia” abstract No. 3160 and poster NR10-47, American Psychiatric Association 166th Annual Meeting 2013 (APA 2013), May 18-22, 2013, San Francisco, Calif., USA)) or for other phases in the disease (e.g. residual symptoms);
(b) epilepsy, based on acute non-clinical studies with mixed mGlu2/3 receptor agonists (Moldrich et al. Eur J Pharmacol. 2003, 476, 3-16; Barton et al. Epilepsy Research 2003, 56, 17-26); continued administration of an mGlu2/3 agonist paradoxically induced seizure activity in long-term toxicology studies (Dunayevich et al. (2008), this paradoxical effect may be related to agonist-induced changes in the sensitivity of the receptor systems (tachyphylaxis); positive allosteric modulators, in contrast, modulate ongoing neurotransmission but are not directly stimulatory, thereby reducing the risk for tachyphylaxis;
(c) drug addiction/dependence (Barrett, Neuropsychopharmacology 2010, 35, 2007-2008; Foster, Curr Drug Abuse Rev 2009, 2, 83-98);
(d) Parkinson's disease (see for example Johnson et al. CNS Neurol Disord Drug Targets 2009, 8, 475-491; Konieczny et al. Naunyn Schmiedebergs Arch. Pharmacol. 1998, 358 (4), 500-502);
(e) pain (Chiechio and Nicoletti, Curr Opin Pharmacol 2012, 12, 28-34; Jones et al. Neuropharmacology 2005, 49, 206-218; Neugebauer, [Review] Pain 2002, 98 (1-2), 1-8; Simmons et al. Pharmacology, Biochemistry and Behavior 2002, 73, 419-427); (f) sleep disorders (Ahnaou et al. European Journal of Pharmacology 2009, 603, 62-72);
(f) Huntington's disease (based on a potential disease modifying effect (Schiefer et al. Brain Res 2004, 1019, 246-254) which is to be confirmed further); and
(g) depression (although no efficacy signal was detected on the primary outcome measure, adjunctive administration of JNJ-40411813/ADX71149 in the dose range tested in a multicenter, double-blind, placebo-controlled study in adults with major depressive disorder with anxiety symptoms showed efficacy signals on several secondary outcome measures of both depression and anxiety (Kent et al. “Efficacy and Safety of a Novel mGlu2 Receptor Positive Allosteric Modulator as an Adjunctive Treatment to an SSRI/SNRI in the Treatment of Anxious Depression”, Abstract to poster and oral presentation, American Society of Clinical Psychopharmacology (ASCP) 2014 Annual Meeting, Jun. 16-19, 2014 Westin Diplomat, Hollywood, Fla.)).
A new avenue for developing selective compounds acting at mGluRs is to identify compounds that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site.
Positive allosteric modulators of mGluRs have emerged recently as novel pharmacological entities offering this attractive alternative.
It was demonstrated that such compounds do not activate the receptor by themselves. Rather, they enable the receptor to produce an increased response to a concentration of glutamate, which by itself induces a minimal response. Mutational analysis has demonstrated unequivocally that the binding of mGluR2 positive allosteric modulators does not occur at the orthosteric site, but instead at an allosteric site situated within the seven transmembrane region of the receptor.
Animal data suggest that positive allosteric modulators of mGluR2 have effects in anxiety and psychosis models similar to those obtained with orthosteric agonists. Allosteric modulators of mGluR2 were shown to be active in fear-potentiated startle (Johnson et al. J Med Chem 2003, 46, 3189-3192; Johnson et al. Psychopharmacology 2005, 179, 271-283), and in stress-induced hyperthermia models of anxiety (Johnson et al. 2005). Furthermore, such compounds were shown to be active in reversal of ketamine—(Govek et al. Bioorg Med Chem Lett 2005, 15(18), 4058-4072) or amphetamine—(Galici et al. J Pharm Exp Ther 2005, 315(3), 1181-1187) induced hyperlocomotion, and in reversal of amphetamine-induced disruption of prepulse inhibition of the acoustic startle effect (Galici et al. 2005) models of schizophrenia.
JNJ-40411813/ADX71149, an mGlu2 PAM (which in rat also displays 5-HT2Aantagonism activity due to a rat-specific metabolite) has undergone clinical trials for the treatment of schizophrenia, and anxiety-depression (see for instance www. Clinicaltrials.gov). Non-clinical data in the lactate-induced panic model in rodents suggests that it could have potential in the treatment of further anxiety disorders such as panic disorder and phobias, such as agoraphobia (Shekhar et al. Neuropsychopharmacology 2013, 38, S435-S593 (W220). JNJ-40411813 was also observed to reduce craving and improve smoking cessation-induced deficits in attention and episodic memory versus placebo (Salih et al. Journal of Psychopharmacology, submitted) and showed an efficacy signal in S-ketamine-induced negative symptoms in healthy volunteers and patients with predominant negative symptoms of schizophrenia (De Boer et al. Society of Biological Psychiatry 68th Annual Scientific Convention of Society of Biological Psychiatry, May 16-18, 2013, Hilton Union Square, San Francisco, Calif., Abstract 2013-P-1060-SOBP).
Positive allosteric modulators enable potentiation of the glutamate response, but they have also been shown to potentiate the response to orthosteric mGluR2 agonists such as LY379268 or DCG-IV. These data provide evidence for yet another novel therapeutic approach to treat the above mentioned neurological and psychiatric diseases involving mGluR2, which would use a combination of a positive allosteric modulator of mGluR2 together with an orthosteric agonist of mGluR2.
Various compounds have been described as mGluR2 positive allosteric modulators. WO2010/130424, WO2010/130423, WO2010/130422, and WO2012/062750, WO2012/062751, and WO2012/062759, published on 18 Nov. 2010 and 18 May 2012, respectively, disclose 1,2,4-triazolo[4,3-a]pyridine derivatives as mGluR2 positive allosteric modulators.